Polymer coated genetically modified Salmonella enterica serovar agona as tumour targeting agent
Conventional tumour therapies pose significant adverse effects to the patients and this brings the need for the development of therapy that is more tumour specific while not affecting the patients negatively. Bacterial mediated tumour therapy is now studied intensely in hope of finding a therapy...
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| Format: | Thesis |
| Language: | English |
| Published: |
2021
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| Online Access: | http://ethesis.upm.edu.my/id/eprint/16170/1/FPSK%202021%2035%20T.pdf |
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| Summary: | Conventional tumour therapies pose significant adverse effects to the patients and
this brings the need for the development of therapy that is more tumour specific
while not affecting the patients negatively. Bacterial mediated tumour therapy is
now studied intensely in hope of finding a therapy that accumulate in tumours
specifically while activating the patient's system to eliminate tumours more
efficiently. Utilising bacteria as tumour therapy is found to be attractive, as these
organisms could be genetically modified to be less pathogenic and express tumour
suppressing proteins and in case of severe infections antibiotics could be used.
Salmonella Agona (S. Agona) had been shown to have similar tumour suppression
capabilities as Salmonella Typhimurium (S. Typhimurium) with reduced systemic
effects to the tumour-bearing mice. S. Agona was then genetically modified to have
B D B D genes attenuated (BDLA S. Agona) which showed no
clinical signs of systemic infections in dogs, better efficacy to suppress tumours
compared to other S. Agona auxotrophs and reduced virulence when tested in
tumour-bearing mice. However, it was observed that multiple administrations of
the treatment did not increase tumour suppression efficacy, suggesting immunity of
the patients reduces the tumour suppression capacity of the BDLA S. Agona strain.
The ubiquitous nature of the strain could mean that most of individuals are exposed
to the strain and have Salmonella-specific antibodies that could reduce tumour
targeting and suppression capabilities. A strategy to overcome this is by
encapsulating the bacteria in biodegradable polymers, such as Poly(allylamine
hydrochloride) (PAH) to allow the strain to escape neutralising antibodies and
possibly improve accumulation in tumours. This study aims to investigate the use
of PAH coating on the BDLA S. Agona to enhance its capabilities as tumour
targeting and suppressing agent and to evaluate the cytokine profiles and
histopathology following the PAH-coated BDLA S. Agona treatment in naïve and
immunised tumour-bearing mice. The 5mg/mL PAH-BDLA S. Agona treatment
showed improvement in tumour targeting capabilities in naïve mice with 1.038 times more accumulation in tumours compared to BDLA S. Agona treated naïve
mice. The 5mg/mL PAH-BDLA S. Agona treatment also showed improved tumour
suppression capabilities in immunised mice, especially on day 12 (T/C ratio of
0.65) and day 15 with mean tumour volume (0.6 fold) and relative tumour growth
(0.77 fold) compared with BDLA S. Agona treated group. From the H&E analysis,
it is observable that immunised subjects receiving 5mg/mL PAH-BDLA S. Agona
showed no inflammation and few microabscesses in liver, smallest lymphoid
follicles in the spleens and reduced lymphoid aggregate in small intestines.
5mg/mL PAH-BDLA S. Agona treatment showed the least increment in cytokines
systemically (mean of IL- -
subjects, while statistically significant at p < 0.05 for induction of TNFpg/
gm) in tumours was observed in naïve subjects which is beneficial in tumour
suppression. This study justifies the use of 5mg/mL PAH-BDLA S. Agona as
tumour therapy and future development as drug delivery agent as it showed
improved tumour targeting and suppressing capabilities with lesser systemic effects
to subjects. |
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